Pharmacokinetics and diuretic effect of furosemide after single intravenous, oral tablet, and newly developed oral disintegrating film ...
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Koh et al. BMC Veterinary Research (2021) 17:295
https://doi.org/10.1186/s12917-021-02998-4
RESEARCH Open Access
Pharmacokinetics and diuretic effect of
furosemide after single intravenous, oral
tablet, and newly developed oral
disintegrating film administration in
healthy beagle dogs
Suk-Kyu Koh1†, Jong-Woo Jeong2†, Seo-In Choi1, Rae Man Kim3, Tae-Sung Koo2, Kwan Hyung Cho3* and
Kyoung-Won Seo4*
Abstract
Background: Furosemide, a diuretic that acts on the loop of Henle, is commonly used to treat congestive heart
failure in veterinary medicine. Some owners have difficulty in administering oral tablet medication to animal
patients, which leads to noncompliance, especially during long-term administration. Oral disintegrating film (ODF)
has the advantages of easy administration via a non-invasive route, rapid dissolution, and low suffocating risk. The
objective of this study was to research the pharmacokinetic (PK) profiles and diuretic effect of furosemide after
intravenous (IV), orally uncoated tablet (OUT), and newly developed ODF administration in healthy beagle dogs. In
this study, a furosemide-loaded ODF (FS-ODF) formulation was developed and five beagle dogs were administered
a single dose (2 mg/kg) of furosemide via each route using a cross-over design.
Results: The most suitable film-forming agent was sodium alginate; thus, this was used to develop an ODF for easy
drug administration. No significant differences were detected in the PK profiles between OUT and FS-ODF. In the
blood profiles, the concentration of total protein was significantly increased compared to the baseline (0 h),
whereas no significant difference was detected in the concentration of creatinine and hematocrit compared to the
baseline. FS-ODF resulted in a similar hourly urinary output to OUT during the initial 2 h after administration. The
urine specific gravity was significantly decreased compared to the baseline in each group. The peak times of urine
electrolyte (sodium and chloride) excretion per hour were 1 h (IV), 2 h (OUT), and 2 h (FS-ODF).
* Correspondence: chokh@inje.ac.kr; kwseo@snu.ac.kr
†
Suk-Kyu Koh and Jong-Woo Jeong contributed equally to this work.
3
College of Pharmacy and Inje Institute of Pharmaceutical Sciences and
Research, Inje University, 50834 Gimhae, Republic of Korea
4
Department of Veterinary Internal Medicine, College of Veterinary Medicine,
Seoul National University, 08826 Seoul, Republic of Korea
Full list of author information is available at the end of the article
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data made available in this article, unless otherwise stated in a credit line to the data.Koh et al. BMC Veterinary Research (2021) 17:295 Page 2 of 11 Conclusions: These results suggest that the PK/PD of furosemide after administration of newly developed FS-ODF are similar to those of OUT in healthy dogs. Therefore, the ODF formulation has the benefits of ease and convenience, which would be helpful to owners of companion animals, such as small dogs (< 10 kg), for the management of congestive heart failure. Keywords: Canine, Furosemide, Loop diuretic, Oral film, Tablet, Conventional administration, Congestive heart failure, Diuresis, Noncompliance Background sildenafil citrate sublingual tablet to treat pulmonary ar- Furosemide, a diuretic commonly used in veterinary and terial hypertension, nitroglycerin ointment to treat CHF, human medicine, is recommended as first-line therapy transdermal tulobuterol patch for bronchodilation, and in the management of congestive heart failure (CHF) [1, transdermal beta-blocker (bisoprolol) patch to reduce 2]. It is used in animals for the treatment of pulmonary postoperative atrial fibrillation [19–22]. edema, udder edema, hypercalciuric nephropathy, The oral disintegrating film (ODF) offers several bene- uremia, and hypertension. Additionally, it reduces the fits especially in children, including easy administration incidence of sterile hemorrhagic cystitis associated with via a non-invasive route, fast dissolution, and no risk of cyclophosphamide administration in dogs and is used as choking [23], that also can be utilized in veterinary adjunctive therapy in hyperkalemia [2–10]. The pharma- medicine. Moreover, sublingual and oral furosemide ad- cokinetics and pharmacodynamics properties of loop di- ministration differ in pharmacokinetic and pharmacody- uretics, including furosemide after IV and oral (PO) namic results in humans [11]; the sublingual route may administration, have been well investigated in both hu- provide therapeutic advantages over the oral route, espe- man and veterinary medicine [5, 8, 11–14]. cially in patients with CHF. In veterinary medicine, there Furosemide decreases the absorption of electrolytes in is a study on the diuretic effect of furosemide according the luminal surface of the thick ascending loop of Henle to the IV, SC, PO, and constant rate infusion (CRI) via the deactivation of the Na+-K+-2Cl− cotransporter. routes in dogs [18]. The study on furosemide adminis- Thus, this drug increases the renal excretion of sodium, tration using sublingual bioadhesive film showed ex vivo potassium, chloride, and water [8]. Additionally, fur- mucoadhesion using the buccal mucosa and permeabil- osemide causes renal venodilation, increases glomerular ity using the tongue excised from slaughtered pigs [24]. filtration rate, increases renal blood flow, and decreases And no alternative route of administration of furosemide peripheral resistance. Furthermore, furosemide activates has been reported, except for a study that the thera- the renin-angiotensin-aldosterone-system and sympa- peutic effect of the transdermal application of furosem- thetic nervous system [15–17]. Although furosemide in- ide to cats is negligible [7]. However, there are no creases renin secretion, owing to its effects on the announced studies on alternative administration routes nephron, increases in sodium and water retention do in dogs. Despite there is a need for formulations that not occur [8]. can be safely administered to and easily absorbed by ani- Conventional routes of furosemide administration are mals, ODFs for use in dogs (especially small dogs) and intravenous (IV), intramuscular (IM), subcutaneous cats have not been developed. (SC), or oral (PO). Unless an acute heart failure event The first objective of this study was to develop a suit- occurs, PO administration is indicated in most cases that able film applicable containing furosemide, which pro- require long-term use in stable patients [8, 9, 18]. The vide advantages over conventional administration routes onset time (IV, 5 min), elimination half-life (IV, 1– in veterinary medicine. The second objective of this 1.5 h), duration (IV, 3–6 h), and peak urine output (IV study was to compare the PKs and diuretic effect of fur- and SC, 1 h; PO, 2 h) of furosemide have been shown in osemide after newly developed furosemide-loaded ODF previous experiments in dogs [8]. (FS-ODF), conventional oral commercial tablet, and IV However, some owners have difficulty administering administration. We hypothesized that the newly devel- oral tablet medications, which leads to noncompliance, oped FS-ODF would have similar drug when compared especially with drugs that require long-term administra- to oral tablets when administered at the same dose. . tion. Particularly with cats, it is often difficult to admin- ister pills or capsules. Beyond the conventional administration routes and formulations, studies have Results been conducted to identify options with similar efficacy Based on previous studies, film-forming agent and other that can be easily administered. For human cardiac dis- excipients, including the plasticizer, solubilizer, disinte- ease, these studies have led to the development of the grant, sweetener, and solvent, were investigated for the
Koh et al. BMC Veterinary Research (2021) 17:295 Page 3 of 11
most suitable agent and sodium alginate was selected to
form the ODF.
The FS-ODF was prepared using the formulation
shown in Table 1. Each FS-ODF had a size of 2 × 3 cm2
and weight of each film is 50 mg. This film had a homo-
geneous surface with some turbidity (Fig. 1). The mean
weight of the film and drug content were 51.75 ±
2.25 mg and 97.63 % ± 1.87 %, respectively The disinte-
gration time was 33.5 ± 4.5 s in water and the bending
count, which represents tensile strength, was 4.4 ± 0.5.
In the dissolution test, FS-ODF showed a pH-
dependent curve (Fig. 2). The dissolution rate at pH 4.0
(96.75 %) and pH 6.8 (98.48 %) was higher than that at
pH 1.2 (3.54 %) after 60 min. The dissolution rate at pH
1.2 was less than 10 % after 120 min. However, FS-ODF
reached complete dissolution of more than 95 % at pH
4.0 and pH 6.8 within 60 min.
The dose of furosemide via all three routes was well-
tolerated in all dogs. The vital signs on physical examin-
ation and behavior did not change during the study period.
PK data of furosemide after the three routes of admin-
istration are summarized in Table 2 and presented in
Fig. 3. No significant differences were detected between
the orally uncoated tablet (OUT) and FS-ODF. In our
study, the PK results of plasma furosemide showed a
mean Cmax of 9.65 µg/mL (IV, C0), 0.61 µg/mL (OUT),
and 0.81 µg/mL (FS-ODF), mean AUClast of 2.67 µg·h/ Fig. 1 Representative appearance of furosemide-loaded orally
disintegrating film. Legend: No content
mL (IV), 1.16 µg·h/mL (OUT), and 1.11 µg·h/mL (FS-
ODF), and mean T1/2 of 2.07 h (IV), 3.44 h (OUT), and
2.64 h (FS-ODF). administration, and the serum chloride concentration was
Plasma concentration of total protein was significantly significantly decreased 2 h after IV and OUT administra-
increased 4 h after IV, 1–4 h after OUT, and 2–4 h after tion. Compared to that at baseline, the serum sodium con-
FS-ODF administration compared to baseline. However, centration did not change significantly over time (Table
the plasma blood urea nitrogen (BUN) concentration was 4). Additionally, indirect systolic blood pressure was not
significantly increased 1–2 h after IV and decreased 1 h different among application routes nor time points.
and 4–8 h after FS-ODF administration compared to The hourly urine output (HUO) and accumulated
baseline. The plasma concentrations of creatinine and urinary output are shown in Table 5. The HUO in the
hematocrit were not significantly different compared to 1–2 h after administration was increased significantly
the baseline at any time point (Table 3). Moreover, the compared to the baseline in each group. The HUO peak
serum potassium concentration was significantly de- of IV administration was high and early, whereas that of
creased 1–6 h after IV and OUT and 1–8 h after FS-ODF OUT and FS-ODF administration was broader and ap-
peared later. The HUO was increased 1 h after IV ad-
Table 1 Formulation of FS-ODF ministration, then returned to the baseline level after
Purpose of use Formulation (mg) 4 h. The HUO for OUT and FS-ODF was increased 1–
Acitive ingredient Furosemide 20
2 h after administration and returned to the baseline
level after 6 h. The mean duration of diuresis until the
Film forming agent Sodium alginate 14
return to baseline levels after IV, OUT, and FS-ODF ad-
Plasticizer Glycerin 4 ministration was 4.1 h, 5.72 h, and 5.24 h, respectively.
PEG 400 4 Similar value of HUO were observed between OUT and
Solubilizer Tween 80 1 FS-ODF during initial 2 h after administration. The total
Sweetener D-Sorbitol 1 urine output was 24.65 mL/kg, 30.9 mL/kg, and 25.4
Disintegrant Crospovidone 6
mL/kg during 8 h after IV, OUT, and FS-ODF adminis-
tration, respectively. -Urine-specific gravity (USG) and
Total weight (mg) 50
urine electrolyte excretion per hour (UEEH) are shown inKoh et al. BMC Veterinary Research (2021) 17:295 Page 4 of 11
Fig. 2 Dissolution profiles of furosemide-loaded orally disintegrating film at pH 1.2, pH 4.0, pH 6.8. (n = 4). Legend: No content
Table 6. The USG was significantly decreased after admin- the conventional routes of furosemide administration,
istration in all groups but returned to the baseline after PO administration is the most common route for long-
8 h. The UEEH was significantly increased 1–2 h after ad- term management in veterinary patients with CHF [8,
ministration in all groups. The peak times of sodium and 9]. However, in the case of home care, oral tablet admin-
chloride UEEH were 1 h, 2 h, and 2 h, whereas those of istration may be limited by low patient cooperation and
potassium UEEH were 1 h, 1 h, and 2 h, after IV, OUT, it is difficult to use other traditional administration
and FS-ODF administration, respectively. routes, such as IM, SC, and IV. For the reasons men-
tioned earlier, we studied a useful alternative routes that
could be applied to veterinary medicine.
Discussion Usually, ODFs disintegrate within 1 min in the oral
To the authors’ knowledge, this study is the first to com- cavity owing to contact with the saliva, which results in
pare the PK parameters and diuretic effect of IV, OUT rapid absorption. Furthermore, when administered via
and ODF administration of furosemide in dogs. Among buccal or sublingual routes, there are advantages of high
Table 2 Pharmacokinetic parameters of furosemide (2 mg/kg) based on route of administration in beagle dogs
Pharmacokinetic parameters IV OUT FS-ODF P
OUT vs. FS-ODF
Cmax (μg/mL) 9.65 ± 1.63 (10.35) 0.61 ± 0.31 (0.69) 0.81 ± 0.81 (0.58) 0.619
Tmax (h) 0.00 1 (0.5-1.5) 0.75 (0.25-1) 0.130
T1/2 (h) 2.07 ± 0.76 (1.63) 3.44 ± 1.79 (2.86) 2.64 ± 0.75 (2.46) 0.602
MRT (h) 0.90 ± 0.25 (0.78) 5.08 ± 1.67 (4.13) 3.47 ± 0.76 (3.55) 0.128
AUCinf (μg·h/mL) 2.74 ± 0.25 (2.60) 1.50 ± 0.73 (1.72) 1.25 ± 0.68 (1.34) 0.493
AUClast (μg·h/mL) 2.67 ± 0.26 (2.56) 1.16 ± 0.46 (1.44) 1.11 ± 0.63 (1.08) 0.734
CL (mL/h/kg) 735.7 ± 63.84 (768.98) - - -
Vss (mL/kg) 667.5 ± 222.6 (597.82) - - -
BA (%) - 54.98 ± 26.51 (62.74) 45.73 ± 25.02 (48.82) 0.493
Cmax maximum plasma concentration, Cmax,IV = C0, Tmax time at the maximum concentration, T1/2 elimination half-life, MRT mean residence time, AUCinf area under
the curve from time zero to time of infinity measurable concentration, AUClast area under the curve from time zero to time of last measurable concentration, BA
bioavailability, CL elimination clearance, Vss volume of distribution at steady state, IV intravenous, OUT orally uncoated tablet, FS-ODF furosemide-loaded orally
disintegrating film. Results are presented as mean ± SD (median). However, Tmax, a categorical variable, expressed as median and range. (*), values are
significantly different (P < 0.05); (**) values are significantly different (P < 0.01)Koh et al. BMC Veterinary Research (2021) 17:295 Page 5 of 11
Fig. 3 Mean plasma furosemide concentration for each group. Legend: A Comparison of time course change in plasma concentration following
2 mg/kg furosemide administration in intravenously (IV), orally uncoated tablet (OUT) and furosemide-loaded orally disintegrating film (FS-ODF)
group. B OUT and FS-ODF are represented by a line graph in (A). IV, (●); OUT, (□); FS-ODF, (◇)
permeability and bypassing first-pass metabolism [23]. furosemide in the final preparation suspension enabled
In this study, the ODF dissolved in the mouths of dogs the homogeneous and desirable film surface and might
quickly without water, which indicates that the ODF for- have reduced weight variation and content loss [26]. The
mulation is beneficial with regard to rapid dissolution, formulation was optimized, with a disintegration time of
absorption, and ease of drug administration in veterinary less than 40 s, owing to the presence of crospovidone as
patients. Therefore, a low-dose FS-ODF formulation for a disintegrant. Rapid disintegration to small particles in
small animals was developed. the mouth is an essential property to ensure the good
Based on our research results, it was decided to use usability of a film [27]. Moreover, the bending count was
sodium alginate as film-forming agent containing fur- in an acceptable range and showed the flexibility of the
osemide. Then, 20 mg of furosemide (a high ratio; 40 %, film. Overall, FS-ODF had suitable film properties in
w/w) was loaded per sheet, which was cut depending on terms of appearance, drug content, disintegration time,
the body weight of the dog to reach a dose of 2 mg/kg. and tensile strength.
These physical specifications were achieved for conveni- In the dissolution test, FS-ODF showed a pH-
ence of use in small animals, such as small dogs (< dependent curve because furosemide has a highly pH-
10 kg) or cats [25]. The small and uniform particles of dependent solubility. Furosemide is a weak acid (pKa =
Table 3 Hematocrit and biochemistry profile following single dose of furosemide (2 mg/kg) administration
Baseline Time (h)
1 2 4 6 8
Hematocrit(%) IV 40.46 ± 9.43 41.36 ± 5.43 38.52 ± 6.84 39.06 ± 7.43 39.02 ± 6.01 40.22 ± 5.35
OUT 38.98 ± 4.18 39.10 ± 3.16 38.52 ± 3.50 38.64 ± 3.75 38.72 ± 4.04 40.12 ± 3.94
FS-ODF 41.94 ± 5.19 41.02 ± 6.17 40.20 ± 6.48 41.44 ± 4.21 41.58 ± 6.30 40.54 ± 7.81
** **
BUN (mg/dL) IV 17.10 ± 6.33 17.50 ± 5.60 17.20 ± 5.57 16.72 ± 5.25 16.20 ± 5.21 15.94 ± 5.23
OUT 21.84 ± 9.99 20.82 ± 9.12** 20.22 ± 8.99 19.04 ± 7.96 17.52 ± 6.25 16.60 ± 5.83
FS-ODF 18.96 ± 6.39 18.68 ± 6.15** 18.16 ± 6.10 17.30 ± 5.90** 16.14 ± 5.28* 15.41 ± 4.72*
Cr (mg/dL) IV 0.72 ± 0.24 0.68 ± 0.19 0.68 ± 0.24 0.68 ± 0.19 0.72 ± 0.13 0.68 ± 0.23
OUT 0.72 ± 0.29 0.70 ± 0.25 0.68 ± 0.23 0.66 ± 0.23 0.68 ± 0.16 0.66 ± 0.18
FS-ODF 0.72 ± 0.13 0.74 ± 0.19 0.68 ± 0.22 0.70 ± 0.19 0.72 ± 0.19 0.70 ± 0.20
Total protein (mg/dL) IV 5.90 ± 0.36 6.32 ± 0.29** 6.18 ± 0.36** 6.10 ± 0.30* 6.04 ± 0.25 6.04 ± 0.34*
OUT 5.74 ± 0.29 6.02 ± 0.25** 6.10 ± 0.38** 6.10 ± 0.31* 5.94 ± 0.34 6.00 ± 0.29*
FS-ODF 6.06 ± 0.18 6.30 ± 0.10** 6.38 ± 0.18** 6.26 ± 0.17* 6.30 ± 0.20 6.34 ± 0.05*
Data are described as mean ± SD values. IV intravenous, OUT orally uncoated tablet, FS-ODF furosemide-loaded orally disintegrating film, BUN Blood urea nitrogen,
Cr Creatinine. The p-values are significantly different (*p < 0.05, **p < 0.01) compared to the baselineKoh et al. BMC Veterinary Research (2021) 17:295 Page 6 of 11
Table 4 Serum electrolyte concentration following furosemide (2 mg/kg) administration in beagle dogs
Baseline Time (h)
1 2 4 6 8
Serum sodium excretion (mmol) IV 151.26 ± 4.06 148.14 ± 1.46 148.04 ± 1.13 150.60 ± 2.10 147.74 ± 4.79 148.52 ± 1.30
OUT 150.34 ± 2.62 153.56 ± 7.59 150.14 ± 1.48 149.12 ± 1.08 151.92 ± 5.29 149.84 ± 1.44
FS-ODF 150.94 ± 2.97 155.20 ± 9.26 150.06 ± 2.12 148.98 ± 6.06 153.46 ± 9.29 148.56 ± 1.09
* ** ** **
Serum potassium excretion (mmol) IV 4.48 ± 0.15 4.19 ± 0.17 3.97 ± 0.29 4.12 ± 0.29 4.04 ± 0.31 4.15 ± 0.42
OUT 4.51 ± 0.34 4.43 ± 0.41* 3.97 ± 0.14** 4.05 ± 0.23** 4.04 ± 0.28** 4.05 ± 0.27
** ** ** *
FS-ODF 4.43 ± 0.32 4.08 ± 0.36 3.92 ± 0.28 4.09 ± 0.37 4.13 ± 0.41 4.05 ± 0.23*
*
Serum chloride excretion (mmol) IV 110.66 ± 4.20 106.46 ± 1.41 105.96 ± 1.33 107.64 ± 2.01 104.34 ± 4.25 106.36 ± 0.80
*
OUT 110.28 ± 3.38 111.56 ± 8.26 107.52 ± 1.61 105.88 ± 0.58 107.76 ± 3.43 106.50 ± 1.35
FS-ODF 110.22 ± 3.30 112.74 ± 7.69 106.84 ± 1.82 106.04 ± 4.56 109.96 ± 7.89 106.20 ± 1.08
Results are presented as mean ± SD. IV intravenous, OUT orally uncoated tablet, FS-ODF furosemide-loaded orally disintegrating film. The p-values are significantly
different (*p < 0.05, **p < 0.01) compared to the baseline
3.48) with a carboxylic acid functional group and its PO administration has a slower onset than that after IV
aqueous solubility increases as the pH increases from and SC administration [32]. Furthermore, the bioavail-
0.18 mg/mL (pH 2.3) to 13.36 mg/mL (pH 10.0) [28]. ability of furosemide is approximately 77 % in dogs and
Thus, in this study, the dissolution rate was in the order 60–65 % in humans after PO administration [8, 13, 29].
of pH 6.8 > pH 4.0 > > pH 1.2 within 60 min. FS-ODF The diuretic effect of furosemide continues 1–2 h after
showed immediate-release on the curve (Fig. 2), with IV injection. Moreover, the absorption of furosemide is
high dissolution rates at pH 4.0 and pH 6.8 owing to the influenced by the pH and the existence of binding pro-
rapid disintegration time of less than 1 min. Therefore, teins in the stomach [18, 33, 34]. Although furosemide is
FS-ODF was sufficient, in terms of disintegration time slowly absorbed in the small intestine, it is absorbed rap-
and dissolution rate, for administration to small animals. idly in the stomach because of the acid environment.
In dogs and humans, the diuretic effect caused by fur- The absorption of furosemide in the gastrointestinal
osemide continues for 3 h after IV injection. The con- tract of patients with CHF may be lower than normal
centration of furosemide initially exceeds the number of [35]. Generally, in patients with CHF, absorption delay
Na+-K+-2Cl− cotransporters in the loop of Henle after may be the result of increased motility, reduced perfu-
IV administration and are excreted in the urine. There- sion, or mucosal edema of intestine [36, 37].
after, the furosemide concentration declines under The PKs of furosemide determine the therapeutic ef-
therapeutic concentrations [29–31]. fect, entry rate of drug into the blood and urine, and on-
Additionally, the bioavailability of furosemide is differ- set and duration of effects, all of which are altered by
ent depending on the administration method. For ex- the method of administration [18, 29, 30]. Both OUT
ample, when administered orally, the first-pass effect, and FS-ODF administration showed a slower onset and
related to the extent of gastrointestinal absorption and a longer elimination half-life than IV administration.
metabolism, plays a major role in the bioavailability of Previous studies have shown a half-life of 0.5–1 h after
furosemide. Also, the first-pass effect varies by species IV administration, whereas the half-life has been re-
and individual. The diuretic effect of furosemide after ported as 30 min in the major disposition phase and
Table 5 Hourly urine output and cumulative urine output after furosemide administration via different routes
Baseline Time (h)
1 2 4 6 8
Hourly urinary output (ml/h) IV 8.45 ± 2.82 147.20 ± 34.05** 74.60 ± 15.61** 9.70 ± 3.93 7.10 ± 3.11 6.20 ± 3.68
** **
OUT 16.40 ± 22.28 88.80 ± 94.10 128.80 ± 51.09 34.30 ± 16.90 13.50 ± 5.51 6.60 ± 4.59
FS-ODF 12.66 ± 6.97 71.40 ± 41.93* 121.20 ± 61.49* 18.0 ± 8.96 9.40 ± 4.48 6.70 ± 2.31
Accumulatedurinary output (ml) IV 13.0 ± 4.53 160.20 ± 37.16** 234.80 ± 47.07** 254.20 ± 51.28** 268.4 ± 57.05** 288.6 ± 55.76**
** ** ** **
OUT 26.20 ± 32.22 115.0 ± 124.80 243.80 ± 151.63 312.40 ± 139.36 339.4 ± 135.60 359.8 ± 134.75**
FS-ODF 27.0 ± 16.90 98.40 ± 41.97* 219.60 ± 89.41** 255.60 ± 91.68** 274.40 ± 87.68** 293.60 ± 99.60**
Data are described as mean ± SD values. IV intravenous, OUT orally uncoated tablet, FS-ODF furosemide-loaded orally disintegrating. The p-values are significantly
different (*p < 0.05, **p < 0.01) compared to the baselineKoh et al. BMC Veterinary Research (2021) 17:295 Page 7 of 11
Table 6 Urine-specific gravity and urine electrolyte excretion after furosemide (2 mg/kg) administration
Baseline Time (h)
1 2 4 6 8
Urine-specific gravity IV 1.040 ± 1.012 ± 1.007 ± 1.011 ± 1.020 ± 1.030 ± 0.007
0.010 0.002** 0.001** 0.002** 0.004*
OUT 1.039 ± 1.032 ± 1.012 ± 1.010 ± 1.017 ± 1.022 ± 0.007
0.009 0.015** 0.006** 0.003** 0.006*
FS- 1.045 ± 1.022 ± 0.013* 1.009 ± 1.014 ± 1.020 ± 1.025 ±
ODF 0.007 0.002** 0.005** 0.010* 0.009*
Urine sodium excretion per hour (mmol/h) IV 0.64 ± 0.56 17.75 ± 7.21** 8.70 ± 3.52** 0.95 ± 0.47 0.52 ± 0.21 0.35 ± 0.21
OUT 0.95 ± 1.05 11.13 ± 18.88 ± 3.77 ± 1.77 1.22 ± 0.52 0.44 ± 0.22
11.67** 10.01**
FS- 0.93 ± 0.56 8.63 ± 4.63* 17.18 ± 12.01* 1.96 ± 0.94 0.78 ± 0.24 0.48 ± 0.11
ODF
Urine potassium excretion per hour (mmol/ IV 0.31 ± 0.16 3.51 ± 1.17** 1.11 ± 0.32** 0.21 ± 0.10 0.16 ± 0.06 0.16 ± 0.11
h) ** **
OUT 0.92 ± 1.12 4.48 ± 4.48 2.46 ± 1.24 0.63 ± 0.26 0.33 ± 0.18 0.14 ± 0.06
FS- 0.79 ± 0.53 2.40 ± 0.67* 2.70 ± 1.38* 0.41 ± 0.21 0.24 ± 0.13 0.16 ± 0.06
ODF
Urine chloride excretion per hour (mmol/h) IV 0.43 ± 0.11 11.43 ± 3.04** 5.72 ± 1.33** 0.72 ± 0.33 0.32 ± 0.12 0.19 ± 0.08**
OUT 1.04 ± 1.29 8.48 ± 9.14** 10.29 ± 4.41** 2.63 ± 1.36 0.84 ± 0.38 0.25 ± 0.09**
* *
FS- 0.76 ± 0.47 4.89 ± 2.62 9.60 ± 5.21 1.39 ± 0.62 0.53 ± 0.23 0.30 ±0.09
ODF
Data are described as mean ± SD values. IV intravenous, OUT orally uncoated tablet, FS-ODF furosemide-loaded orally disintegrating film. The p-values are
significantly different (*p < 0.05, **p < 0.01) compared to the baseline
approximately 7 h in the slow elimination phase after FS-ODF administration was similar at 5 h. Additionally,
PO administration in dogs [5, 6, 38]. According to an- UEEHs were increased during the initial 2 h after admin-
other PK/PD study in healthy beagle dogs, the half-life istration in all groups. Based on HUO, USG, and UEEH
after PO administration in dogs is 3 h, which is similar results, FS-ODF has equivalent aquaretic, natriuretic,
to the results of the present study [39]. kaliuretic, chloriuretic, and diuretic effects to conven-
In the body, furosemide moves across the renal tu- tional OUT.
bule from the plasma to the lumen of the nephron; This study has a few limitations, which may be over-
thus, furosemide acting on henle’s loop of renal tu- come by further research. First, additional studies using
bule should have a short duration of effects if its different doses and repeating doses are needed because
half-life is short [7]. These results appear to be owing we used only a single dose of furosemide (2 mg/kg). Sec-
to the initial high blood concentration and rapid ond, we only used five healthy intact beagle dogs. Add-
elimination of furosemide after IV administration. In itional studies should be conducted in more dog patients
addition to the route of administration of the drug, it with CHF, renal failure, and delayed intestinal absorp-
should also be considered that the half-life of drugs is tion. Third, since small animals have various body
affected by many factors, including illness status, age, weight ranges, it is necessary to prove that they contain
and other physiological variables [40]. The present a homogeneous dose even when the film is cut to apply
study demonstrates that the PKs after the administra- the recommended diuretic dose.
tion of FS-ODF are similar to those after that of
OUT in healthy dogs. Conclusions
Furthermore, after IV administration, the HUO was In this study, we developed an ODF for small animals
significantly increased and peaked after 1 h, then de- that showed similar PK parameters and diuretic effect
creased gradually to baseline levels. This result was simi- when compared to OUT administration. Collectively,
lar to that of previous studies of the IV route [8]. The the results of this study suggest that the FS-ODF formu-
HUO of OUT and FS-ODF routes were significantly in- lation can be used as an alternative to oral tablets in ani-
creased after 1–2 h and peaked after 2 h. Therefore, FS- mal patients with heart failure and volume overload.
ODF and OUT resulted in a similar HUO during the ini- Therefore, it would be helpful to owners of dogs that re-
tial 2 h after administration. fuse conventional oral medications owing to the poten-
The duration of diuresis (time until return to baseline tial benefits of easy administration and convenient
level after furosemide administration) after OUT and dosage form.Koh et al. BMC Veterinary Research (2021) 17:295 Page 8 of 11
Methods Bending Count
Animals The bending count measured by the number of times it
Five clinically healthy adult beagle dogs (three intact took to split when the film was folded in half repeatedly
males and two intact females) dogs from a research col- with two fingers.
ony at the College of Veterinary Medicine of Chungnam
National University were included in this study. The ani- Weight and Drug Content
mals were 5–9 years of age and weighed 10–13 kg. All The prepared FS-ODF was weighed using balance and
dogs were normal on physical examination, including transferred into 30 mL dilution solution (0.05 N NaOH
systemic blood pressure measurement with a Doppler solution) in 50 mL volumetric flask and dissolved with
device, and within normal ranges on complete blood vortexing. Then, the dilution solution was added to the
count, serum biochemistry panel, serum electrolytes, total volume. This solution of 2 mL was transferred to
and urinalysis. Animals were housed in cages and fed 100 mL volumetric flask and the dilution solution was
commercial food (SUNGBO Pet Healthcare, Seoul, added to the total volume. The final solution was filtered
South Korea) twice daily. Water was provided ad libi- with syringe filter (0.45 μm) and the filtrate was analyzed
tum. This study was approved by the Institutional Ani- by the below HPLC method.
mal Care and Use Committee (IACUC) at Chungnam
National University (approval number, CNU-01189). HPLC Condition
After the study, all dogs were adopted as companion The HPLC analysis of furosemide in the samples was
animals. conducted using a Waters 2695 HPLC system (Waters,
Milford, MA, USA) equipped with a UV-Vis detector
Preparation of FS-ODF (Waters 2487, Waters, Milford, MA, USA). Furosemide
The FS-ODFs were prepared by a simple, easy solvent- was analyzed using the reverse column with C18, 5 μm,
casting method that required no special equipment [41]. 4.5 mm × 25 cm (Shiseido, Tokyo, Japan). The mobile
For lab-scale preparation, as the batch size was 15 FS- phase consisted of water, tetrahydrofuran, and acetic
ODFs, the amount of formulation for 15 FS-ODFs was acid (70:30:1, v/v/v). The HPLC analysis was performed
weighed and used (Table 1). Furosemide and two plasti- with a flow rate of 1.2 mL/min. The injected volume of
cizers were dissolved in 4.5 mL of ethanol, heated in the sample was 20 µL, and UV detection was monitored
80 °C chambers for 30 min. This solution was trans- at 272 nm [43]. Data acquisition and processing were
ferred to a 40 °C chamber to reach temperature equilib- carried out using the Waters LC Solution software.
rium (Solution A). The other excipients, including the
film-forming agent, solubilizer, and sweetener, were dis- Dissolution Test
solved in 10.5 mL of water and the disintegrant was sus- The dissolution test was performed using the USP [35]
pended. This aqueous solution was transferred to 40 °C dissolution apparatus II at pH 1.2 (0.1 N HCl/NaCl buf-
chambers to reach temperature equilibrium (Solution B). fer), pH 4.0 (acetate buffer), pH 6.8 (phosphate buffer)
Solution A was added to Solution B and the mixture was with the media volume of 900 mL at 37.0 ± 0.5 °C. The
stirred at room temperature (22–24 °C) for 30 min to rotational speed was adjusted to 50 rpm. The prepared
obtain a uniform suspension. This suspension was soni- FS-ODF containing furosemide 20 mg in a sample was
cated for 10 min for degassing. The amount of suspen- placed into a dissolution vessel with a sinker [44]. At
sion equivalent to 10.60 films on an area basis was each predetermined interval, the aliquot (5 mL) of the
placed on a Petri dish (9 cm in diameter) and dried in medium was collected and filtered through a membrane
80 °C chambers for 40–45 min. The formed film was filter (pore size: 0.45 μm). The concentration of fur-
peeled off and cut to a predetermined size of 2 × 3 cm2. osemide in the filtrate was determined using the above
HPLC method.
Characterization of FS-ODF
Disintegration time, bending count, weight and drug Study design
content tests for characterization of FS-ODF were each This study was performed using a single-dose, random-
run 5 times. ized, 3-way crossover design. Three methods of furosem-
ide administration were used in each subject with at
Disintegration Time least 7-day washout period between each experiment.
One FS-ODF was placed on a petri dish (9 cm diameter) Animals were fasted for 12 h before the administration
with 15 mL of 37 ℃ water. The time to disintegrate of furosemide and had a free access to water during the
completely was measured by visual observation [42]. The experiment.
absence of any significant floating fragments was consid- Each (random) animals received a furosemide of 2 mg/
ered to be the completion of disintegration. kg via intravenous (IV), orally uncoated tablet (OUT),Koh et al. BMC Veterinary Research (2021) 17:295 Page 9 of 11
furosemide-loaded orally disintegrating film (FS-ODF) mixtures were separated into supernatant and precipi-
routes: (1) Furosemide 2 mg/kg IV (n = 5), (2) OUT for- tant pellet by centrifugation at 17,600 g for 15 min.
mulation of furosemide 2 mg/kg orally (n = 5), (3) FS- Standard samples were prepared by spiking of 5 µL
ODF formulation 2 mg/kg orally (n = 5). working solution (as furosemide; 0, 30, 100, 300, 1,000,
Injections and OUT formulation of furosemide were 3,000, 10,000, 30,000, and 100,000 ng/mL in acetonitrile)
purchased from handok Pharm. Co. (Seoul, South into 45 µL of blank plasma. For a sample analysis, 130
Korea). For oral administration, furosemide OUT and µL of supernatant were transferred into sample vials,
FS-ODF formulation were cut according to body weight and 5 µL of processed sample was directly injected into
of each dog. Also, 22-Gauge IV catheter was used in the HPLC separation system.
cephalic vein for the IV injections. All dogs received no Furosemide and IS were separated by Agilent 1100
other medications before the experiment and during the HPLC system. Chromatographic separation was con-
washout period. ducted on Agilent ZORBAX® phase phenyl column
(5 μm, 2.1 × 50 mm) by 6 mM ammonium formate in
Sample collection 40 % acetonitrile solution.
Blood samples were collected at 0 (serving as baseline), After separation, both analytes were detected by triple
5, 15, 30, 45, 60, 120, 240, 360, 480 min in each adminis- quadrupole mass spectrometer (AB SCIEX API4000
tration routes. All blood samples were obtained from the QTRAP®). Furosemide and IS were monitored under
jugular vein with 23-Gauge 5mL syringe. These samples electrospray ionization negative mode as multiple reac-
were immediately divided into heparinized tubes for bio- tion monitoring, which mass to charge ratio of 329.08−
chemical test, plain tubes for electrolyte analysis and to 284.80− for furosemide and 205.05− to 161.10− for IS,
EDTA-K2 tube for hematocrit. Heparinized plasma and respectively.
serum were separated after centrifugation at 3,000 x g Peak areas integration and quantification were auto-
for 15 min and stored at − 20 °C until analysis. A matically conducted by using Analyst software® (AB
complete blood count, BUN, creatinine (Cr), plasma Sciex) 1.6.2. The retention times of furosemide and ibu-
total protein and serum electrolytes were measured. profen were 0.53 and 0.77 min, respectively.
The urine samples were collected at 0 (serving as base- Concentration-response of furosemide was linear at
line), 1, 2, 4, 6, 8 h in each administration routes. In line ranges from 30 ng/mL to 10 µg/mL (r = 0.9971). The
with previous studies, the bladder was initially emptied validation values, including the precision (coefficient of
2 h before baseline and then collected in 2 h to calculate variance < 5.67 %), accuracy (relative error < 6.39 %) of
baseline hourly urine output (HUO) before furosemide the measurements, were within the acceptable ranges
administration. An indwelling 6–8 Fr balloon Foley cath- given by FDA guidelines.
eter was placed into the urinary bladder at the initiation
of each experiment and the bladder was emptied for Pharmacokinetic analysis
urine volume measured at each time point. Urine sample Temporal profiles of furosemide in beagle were analyzed
was centrifuged (1500 × g, 10 min) and the supernatant with via non-compartmental model using Phoenix Win-
was collected to verify urine-specific gravity and the con- Nonlin 6.2. (Pharsight, USA). The following pharmacoki-
centrations of sodium, potassium and chloride. netic parameters were calculated and compared based
Complete blood count was measured by ADVIA 2120i on the route of administration: Cmax, half-life time,
(SIEMENS corporation, Munich, Germany) and bio- AUCs, CL, Vss, bioavailability (F). The elimination rate
chemistry were measured by Mindray BS-300 (Bio-Med- constant (ke) was determined by linear regression of the
ical Electronics Co., Ltd, Shenzhen, China). Electrolyte semi-log portion of the elimination phase. The elimin-
concentrations in plasma and urine sample were mea- ation half-life (T1/2) was calculated by dividing 0.693
sured by EasyLyte PLUS (MEDICA corporation, Bed- with ke. The area under the plasma concentration versus
ford, USA). time curve from time zero to time of last measurable
concentration (AUClast), the area under the plasma con-
Quantification of furosemide in plasma centration versus time curve from time zero to infinity
Plasma concentration of furosemide were determined by (AUCinf) and the area under the respective first moment
HPLC-MS/MS system. To prepare appropriate assay time curve from time zero to infinity (AUMCinf) were
samples, plasma samples were processed with aceto- calculated based on the linear-up and log-down method.
nitrile to induce precipitation of plasma protein. Firstly, To estimate the elimination clearance (CL) and volume
15 µL of plasma or calibrator sample were treated with of distribution at steady state (Vss), a moment analysis
155 µL of 0.11 µg/mL ibuprofen (internal standard, IS) was conducted. In more detail, CL was gained by divid-
in acetonitrile. And then, sample mixtures were vigor- ing administered dose with AUCinf. Vss was obtained by
ously shaken by vortex mix for 15 min. Finally, sample multiply CL with MRT, which division of AUMCinf byKoh et al. BMC Veterinary Research (2021) 17:295 Page 10 of 11
AUCinf. Fs of film and tablet groups were calculated Chungnam National University (Approval number: CNU-01189). All methods
from the dose normalized AUCPO/AUCIV, respectively. were carried out in accordance with relevant guidelines and regulations.
Consent for publication
Statistical methods Not applicable.
All data were expressed as mean and standard deviation.
Normality test was conducted with Kolmogorov- Competing interests
Smirnov test and pharmacokinetic parameters were an The authors declare that they have no competing interests. The authors
independent t-test. Because the study aimed to compare declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of
orally uncoated tablet with orally disintegrating film, interest.
only the differences between these two formulations of
administration were statistically analyzed. Comparisons Author details
1
Department of Veterinary Internal Medicine, College of Veterinary Medicine,
between baseline (0 h) and various time phases after Chungnam National University, 34134 Daejeon, Republic of Korea. 2Graduate
drug administration were analyzed statistically using the School of New Drug Discovery and Development, Chungnam National
paired t-test. A P-value < 0.05 was considered to be sta- University, 34134 Daejeon, Republic of Korea. 3College of Pharmacy and Inje
Institute of Pharmaceutical Sciences and Research, Inje University, 50834
tistically significant. Statistical analysis was performed Gimhae, Republic of Korea. 4Department of Veterinary Internal Medicine,
using SPSS 25 (SPSS Inc., Chicago, IL, USA). College of Veterinary Medicine, Seoul National University, 08826 Seoul,
Republic of Korea.
Received: 9 April 2021 Accepted: 17 August 2021
Abbreviations
ODF: Oral disintegrating film; PK: Pharmacokinetics; IV: Intravenous;
IM: Intramuscular; OUT: Irally uncoated tablet; FS-ODF: Furosemide loaded-
orally disintegrating film; PO: Oral; CHF: Congestive heart failure; References
CRI: Constant-rate infusion; SC: Subcutaneous; Cmax: Maximum plasma 1. Hori Y, Ohshima N, Kanai K, Hoshi F, Itoh N, Higuchi S. Differences in the
concentration ; C0: Maximum plasma concentration after IV; Tmax: Time at the duration of diuretic effects and impact on the renin-angiotensin-
maximum concentration; T1/2: Elimination half-life; AUCinf: Area under the aldosterone system of furosemide in healthy dogs. J Vet Med Sci. 2010;
curve from time zero to time of infinity measurable concentration; 72(1):13–8.
AUClast: Area under the curve from time zero to time of last measurable 2. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr., Colvin MM, et al. 2017
concentration; F: Fraction of oral dose absorbed (= bioavailability); CL: The ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the
elimination clearance; Vss: Volume of distribution at steady state; MRT: Mean Management of Heart Failure: A Report of the American College of
residence time; USG: Urine specific gravity; ke: Elimination rate constant; Cardiology/American Heart Association Task Force on Clinical Practice
BUN: Blood urea nitrogen; Cr: Creatinine; HUO: Hourly urine output; Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):
UEEH: Urinary electrolytes excretion per hour; HPLC: High-performance liquid e137–e61.
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Plasma and tissue levels of furosemide in dogs and monkeys followingYou can also read
